Ubiquitin-Proteasome System

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Protein degradation via proteasomes is a very sophisticated process. The system is called ubiquitin-proteasome system(UPS) also known as ubiquitin-proteasome pathway(UPP). The entire function is based around protein named ubiquitin of size about 76 aminoacids, 8,5kDa. This protein was first discovered in 1975 without its purpose being explained. Name "ubiquitin" refers to its presence in every eukaryotic cell("ubiquitous" means being everywhere). Ubiquitin takes part in ubiquitination of protein which means it binds to a protein. This is a complex and important reaction to similar extent as other post-translation modification of proteins called phosphorylation[1].

Processes of ubiquitination[edit | edit source]

  1. Ubiquitin in cell is first bonded to ubiquitin-activating enzyme E1 while using energy from ATP.
  2. Then, ubiquitin is transported to ubiquitin-transporting(ubiquiting-conjugating) enzyme E2.
  3. Afterwads, ubiquitin is transported by ubiquitin-ligase E3 to a protein and marks it for degradation(PDG). Ubiquitin-ligase E3 is protein- specific.

In other words, E1 and E2 enzymes have mainly ubiquitin-transporting function and E3 enzymes on the other hand definitely bind ubiquitin to PDG(recognized only by these enzymes). Ubiquitins are bonded to PDG in chain-like structure. E3 enzymes distinguish different PDGs because there are not many types of E1 enzymes(according to [2] there are at least 2 E1 enzymes - Uba6 and Ube1) and not many types of E2 enzymes while there are hundreds of types of E3 enzymes, specializing in PDG preferences.

Ubiquitin-ligases[edit | edit source]

We recognize 2 families of ubiquitin-ligases, being different by presence of active domain: they either contain HECT domain(homologous to E6-Associated Protein C-Terminus), or RING domain(really interesting new gene)[3][4]. Besides the regular E1-E2-E3 cascade, there are other known enzymes, E4, which can support growing of polyubiquitin chain[5].

Ubiquitin bonds[edit | edit source]

The key question is the way of linkage between individual ubiquitins in the chain. Not every polyubiquitin chain is a "death sentence". The most common bond of two ubiquitins in polyubiquitin chain is via lysine 48(so called K48 chains) or lysine 63(so called K63 chains), though there are chains of ubiquitins linked via lysine 6, 11, 27, 29, or 33. Unusually are these branched[6]. Science today is not sure of the meaning of this many signals. Mainly the K48 chains are the "death sentence" while K63 play other roles in cell signalling. Not long ago, it was shown that proteins marked with K63 chains can be recognized by proteazomes and degraded by them[7]. There is also a possibility of K63 chains being reformed into K48 chain[8] while staying on the protein.

Deubiquitination[edit | edit source]

Besides ubiquitination of preoteins, there is opposite process taking place in eukaryotic cell called deubiquitination. Enzymes responsible for this process are called deubiquitinases(DUB for short). We can ditinquish them into 5 groups:

  1. ubiquitin C-terminal hydrolases,
  2. ubiquitin specific proteases,
  3. proteases of domain of Machado-Joseph disease,
  4. proteases of ovarian tumors,
  5. proteases with JAMM domain[9].

Today, there are 75 known DUBs that interact with hundreds of proteins and that play large amount of different roles[10]. Worth noting that one of JAMM domain deubiquitinases, in human cells called Poh1, is part of eukaryotic proteasome and play key role in its function.

Links[edit | edit source]

Related Articles[edit | edit source]

Source[edit | edit source]

  • CVEK, Boris. Od ubikvitinu k antabusu. Britské listy : deník o všem, o čem se v České republice příliš nemluví [online]. 2011, roč. -, s. -, dostupné také z <https://blisty.cz//legacy.blisty.cz/art/56680.html>. ISSN 1213-1792. 

References[edit | edit source]

  1. ↑ KOMANDER, David. The emerging complexity of protein ubiquitination. Biochem Soc Trans [online]. 2009, vol. 37, no. Pt 5, s. 937-53, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/19754430>. ISSN 0300-5127 (print), 1470-8752. 
  2. ↑ JIN, Jianping, Xue LI a Steven P GYGI, et al. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Nature [online]. 2007, vol. 447, no. 7148, s. 1135-8, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/17597759>. ISSN 0028-0836 (print), 1476-4687. 
  3. ↑ ROTIN, Daniela a Sharad KUMAR. Physiological functions of the HECT family of ubiquitin ligases. Nat Rev Mol Cell Biol [online]. 2009, vol. 10, no. 6, s. 398-409, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/19436320>. ISSN 1471-0072 (print), 1471-0080. 
  4. ↑ DESHAIES, Raymond J a Claudio A P JOAZEIRO. RING domain E3 ubiquitin ligases. Annu Rev Biochem [online]. 2009, vol. 78, s. 399-434, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/19489725>. ISSN 0066-4154 (print), 1545-4509. 
  5. ↑ HOPPE, Thorsten. Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all. Trends Biochem Sci [online]. 2005, vol. 30, no. 4, s. 183-7, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/15817394>. ISSN 0968-0004. 
  6. ↑ IKEDA, Fumiyo a Ivan DIKIC. Atypical ubiquitin chains: new molecular signals. 'Protein Modifications: Beyond the Usual Suspects' review series. EMBO Rep [online]. 2008, vol. 9, no. 6, s. 536-42, dostupné také z <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2427391/?tool=pubmed>. ISSN 1469-221X (print), 1469-3178. 
  7. ↑ SAEKI, Yasushi, Tai KUDO a Takayuki SONE, et al. Lysine 63-linked polyubiquitin chain may serve as a targeting signal for the 26S proteasome. EMBO J [online]. 2009, vol. 28, no. 4, s. 359-71, dostupné také z <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646160/?tool=pubmed>. ISSN 0261-4189 (print), 1460-2075. 
  8. ↑ NEWTON, Kim, Marissa L MATSUMOTO a Ingrid E WERTZ, et al. Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies. Cell [online]. 2008, vol. 134, no. 4, s. 668-78, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/18724939>. ISSN 0092-8674 (print), 1097-4172. 
  9. ↑ KOMANDER, David, Michael J CLAGUE a Sylvie URBÉ. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol [online]. 2009, vol. 10, no. 8, s. 550-63, dostupné také z <https://www.ncbi.nlm.nih.gov/pubmed/19626045>. ISSN 1471-0072 (print), 1471-0080. 
  10. ↑ SOWA, Mathew E, Eric J BENNETT a Steven P GYGI, et al. Defining the human deubiquitinating enzyme interaction landscape. Cell [online]. 2009, vol. 138, no. 2, s. 389-403, dostupné také z <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716422/?tool=pubmed>. ISSN 0092-8674 (print), 1097-4172. 
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